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<p>Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.</p>

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Targeting transcription factors through an IMiD independent zinc finger domain

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月14日

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  • Bee Hui Liu,
  • Miao Liu,
  • Sridhar Radhakrishnan,
  • Meng-Yuan Dai,
  • Chaitanya Kumar Jaladanki,
  • Chong Gao,
  • Jing Ping Tang,
  • Kalpana Kumari,
  • Mei Lin Go,
  • Kim Anh L Vu,
  • Junsu Kwon,
  • Hyuk-Soo Seo,
  • Kijun Song,
  • Xi Tian,
  • Li Feng,
  • Justin L Tan,
  • Arek V Melkonian,
  • Zhaoji Liu,
  • Gerburg Wulf,
  • Haribabu Arthanari,
  • Jun Qi,
  • Sirano Dhe-Paganon,
  • John G Clohessy,
  • Yeu Khai Choong,
  • J Sivaraman,
  • Hao Fan,
  • Daniel G Tenen,
  • Li Chai

摘要

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.